St. Jude Children's Research Hospital (SJCRH) initiated an HIV-1 vaccine program five years ago with the conviction that his complex issue would be most effectively addressed through a coordinated, multi-disciplinary approach; the program thus currently involves investigators from SJCRH departments of Immunology , Virology, Infectious Diseases and Structural Biology. The central problem in developing an effective HIV-1 vaccine lies in the antigenic diversity of the virus. The SJCRH HIV-1 vaccine program is unique in explicitly acknowledging this antigenic complexity, by matching the diversity of the pathogen with a diversity of vaccine structures. Thus far, work within the program has resulted in the initiation of an FDA-approved, phase I clinical trial of PolyEnv1, the first HIV vaccine to encompass more than one or two HIV envelope protein structures. The ongoing clinical trial with PolyEnv1 has employed an attenuated live virus vehicle to deliver the vaccine. Preliminary data indicate that modification of the vaccination regime to deliver the cocktail of envelope protein structures represented in PolyEnv1 in a sequential combination of three different immunogenic forms (DNA, attenuated virus and native protein) may result in the generation of neutralizing antibodies at a much increased titer. Specific Aims in Projects 1 (P. Doherty) and 2 (R. Webster) use mouse models to explore the nature of the immune response to combinations of immunogenic forms, to optimize vaccination schemes and to determine the relationship between immunogen complexity and vaccine efficiency. Project 3 (J. Hurwitz) implements the findings of Projects 1 and 2 in a primate (macaques) model of vaccination against immunodeficiency virus infection, as well as developing optimal vaccine manufacturing schemes. Project 4 (K. Slobod) builds on these studies, initiating clinical trials of the safety and effectiveness of vaccines comprised of combinations of immunogenic envelopes.